For repairing cartilages and bones, in addition to autoplasty, there has been practiced a procedure in which a prosthetic material for defected sites of cartilage and bone composed of a combination of a bone morphogenetic protein and a suitable carrier was imbedded in the defected site. In practicing this, the defected site can be exposed on surgical operation to apply a cartilage and bone repairing composition containing a bone morphogenetic protein directly to the defected site, and thus, the materials in a solid form such as blocks, sponges, sheets and the like which are easy to handle have been widely applied. Those in a semisolid form such as gels or pastes can also be used. As the carriers which made such solid or semisolid forms applicable, there have been utilized, for example, metals such as stainless or titanium alloys or collagen and hydroxyapatite (HAP) or a mixture thereof.
On the other hand, an attempt has been made to administer a bone morphogenetic protein for the treatment of bone fracture or osteoarthritis without requiring any surgical operation. This administration mode has been earnestly desired from a viewpoint that non-invasive administration, namely, injection mode, would alleviate pains from patients. However, the injection route of a simple aqueous liquid preparation of a bone morphogenetic protein causes diffusion and disappearance of the drug after administration, and so in order to achieve an effective administration, the bone morphogenetic protein should be retained in the injected site over a certain period of time. In view of the above, there has been envisaged a carrier which may be in a liquid state capable of passing through a needle on administration and then phasetransited to a gel-like state after administration to retain the bone morphogenetic protein in the injected site. Preferably, the carrier may have non-toxicity, a good bio-compatibility and a high bio-absorption in a living body.
Collagen is a known carrier for a bone morphogenetic protein and is confirmed to possess favorable bio-compatibility and bio-absorption (Japanese Patent Publication No. 75425/1993). Collagen with an injectable character has also been reported, which may provide an injectable cartilage and bone morphogenetic material (Japanese Patent Publication Nos. 23322/1995 and 53140/1993). However, collagen now available for the use of medicines is derived from natural sources such as cattle or a pig, so that its properties such as a molecular weight, an amino acid composition and a moisture holding property are not always constant. In addition, it has some side-effects such as antigenicity because it is a heterologous protein to humans. In particular, antigenicity cannot be completely eliminated even when atelocollagen; i.e., collagen from which teropeptide sites are removed, is used (J. American Academy of Dermatology 10, 638-646 and 647-651, 1984 and ibid, 21 1203-1208, 1989).
On the other hand, it was reported that biodegradable polymers such as polylactic acid or polylactic acid-glycolic acid copolymers can be used as pharmaceutical carriers (U.S. Pat. No. 5,385,887 and Japanese Patent Publication No. 22570/1994). However, the biodegradable polymers are in a solid or semisolid state which may maintain a given form, and in view of this, they are classified as a group of applicable materials to surgical operation. Even if an injectable complex can be prepared using such biodegradable polymers, an organic solvent should be employed during the preparation process, which may easily anticipate the problem of inactivation of the active ingredient, a bone morphogenetic protein.